Early on in his lecture, Michael Yaffe serves up an amazing fact: If the distance between each DNA base pair were one foot apart, then each time a cell divided, it would have to copy 568 thousand miles of DNA. This, says Yaffe, is enough to go around the circumference of the earth more than 22 times. What’s more, the cell has to copy its DNA with no errors. “I don’t know (if) civil engineers ... could make 10 miles of road without making single error,” says Yaffe.
Yaffe’s in the business of exploring and mathematically mapping the elaborate signal pathways inside cells that sense broken DNA and coordinate damage response. While studying one such process, cell death in the colon, Yaffe found that the traditional biochemistry approach -- picking one molecule, one stimulus and one readout-- doesn’t work. “It’s like the blind man feeling the elephant’s tail, and saying it’s a long, thin animal.” Yaffe learned that one signal may activate a series of proteins, triggering an amplification loop. A slight change might yield a “whopping response.”
In the 12 hours a cell takes to copy its DNA to create two daughter cells, “it goes to great pains to make sure everything is done correctly. It initiates checkpoints, like border crossings.” Because everyday life exposes DNA to all kinds of damage, cells have evolved “an elaborate surveillance mechanism” to “blow the whistle, signal repair, and recruit repair machinery,” or if damage is too great, essentially commit suicide. If something goes wrong with this mechanism at crucial times during cell division, cancer frequently results.
Just as engineers test integrated circuits at a variety of points, Yaffe came up with a method of testing cell signaling with a variety of proteins. His team came up with 7,000 signaling measurements in 760 dimensions, and 1,400 signal responses. But this data-heavy model for predicting which molecules lead to cell death didn’t satisfy Yaffe. With additional mathematical sleight of hand, Yaffe’s group boiled down the cell signaling measurements to what Yaffe calls two “canonical super axes”: “a global measure of cell stress and death, and another of survival signaling.” He hopes to use this slimmed-down model to think about drugs targeting cancer and inflammation.
About the Speaker
Michael Yaffe
Howard S. and Linda B. Stern Associate Professor of Biology, Department of Biology and the Center for Cancer Research
Michael Yaffe received his Ph.D. in Biophysical Chemistry in 1987, and an M.D. in 1989, both from Case Western Reserve University. Before MIT, he served as a surgeon in teaching hospitals in Cleveland and the Boston area, including the Harvard Medical School.
He received multiple teaching awards from University Hospitals of Cleveland, and earned the 1998 Howard Hughes Physician Scientist Award, and the 1999 Burroughs Wellcome Career Development Award.
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